Materials and methods for the treatment of depression

ABSTRACT

The subject invention provides compounds which are easily metabolized by the metabolic drug detoxification systems. Particularly, fluvoxamine analogs which have been designed to include esters within the structure of the compounds are taught. Also provided are methods of treating depression and affective disorders, such as obsessive compulsive disorder. Pharmaceutical compositions of the fluvoxamine analogs are also taught.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of application U.S. Ser. No.10/273,702, filed Oct. 18, 2002 now U.S. Pat. No. 6,809,116; which is acontinuation of U.S. Ser. No. 09/841,749, filed Apr. 24, 2001, now U.S.Pat. No. 6,469,064; which claims priority from provisional patentapplication U.S. Ser. No. 60/199,343, filed Apr. 24, 2000.

BACKGROUND OF THE INVENTION

Major depression represents one of the most common mental illness,affecting between 5-10% of the population. The disease is characterizedby extreme changes in mood which may also be associated with psychoses.It has generally been found that most antidepressant agents exertsignificant effects on the regulation of monoamine neurotransmitters,including serotonin.

A number of types of antidepressants have been developed in recentyears. Many of these compounds regulate serotonin (5-hydroxytryptamine;5-HT). Trazodone controls the actions of 5-HT while fluoxetine is apotent and selective inhibitor of 5-HT reuptake. 3-Chloroimipraminewhich inhibits both 5-HT and norepinephrine reuptake has beenextensively used as an antidepressant in Europe and Canada. Othercompounds which are of current interest or have been examined asantidepressants include fluvoxamine, citalopram, zimeldine, sertraline,bupropion and nomifensine. Fluvoxamine facilitates serotoninergicneurotransmission via potent and selective inhibition of serotoninreuptake into presynaptic neurons.

The serotonergic neural system of the brain have been shown to influencea variety of physiologic functions, and the compounds of the presentinvention are predicted to have the ability to treat in mammals,including humans, a variety of disorders associated with this neuralsystem, such as eating disorders, depression, obsessive compulsivedisorders, panic disorders, alcoholism, pain, memory deficits andanxiety. Other indications for antidepressants, such as fluvoxamine,include unipolar depression, dysthymia, bipolar depression,treatment-resistant depression, depression in the medically ill, panicdisorder, obsessive-compulsive disorder, eating disorders, socialphobia, and premenstrual dysphoric disorder.

The adverse effects occurring most frequently during treatment withselective serotonin reuptake inhibitors (SSRI(s)) such as fluvoxamineare gastrointestinal disturbances, such as, for example nausea,diarrhoea/loose stools, constipation, with an incidence of 6 to 37%(Drugs 43 (Suppl. 2), 1992). Nausea is the main adverse effect in termsof incidence. These adverse effects, although mild to moderate inseverity, shy some patients away from treatment with SSRIs. Thepercentage of patients withdrawing because of nausea ranges from 3 to 8%of the patients. Moreover it has been frequently observed that afteradministration of SSRIs, patients suffer from dyspepsia. Fluvoxaminealso causes a variety of other adverse effects including anorexia, drymouth, headache, nervousness, skin rash, sleep problems, somnolence,liver toxicity, mania, increased urination, seizures, sweating increase,tremors, and Tourette's syndrome.

Drug toxicity which causes adverse effects is an important considerationin the treatment of individuals. Toxic side effects resulting from theadministration of drugs include a variety of conditions which range fromlow grade fever to death. Drug therapy is justified only when thebenefits of the treatment protocol outweigh the potential risksassociated with the treatment. The factors balanced by the practitionerinclude the qualitative and quantitative impact of the drug to be usedas well as the resulting outcome if the drug is not provided to theindividual. Other factors considered include the clinical knowledge ofthe patient, the disease and its history of progression, and any knownadverse effects associated with a drug.

Drug elimination is the result of metabolic activity upon the drug andthe subsequent excretion of the drug from the body. Metabolic activitycan take place within the vascular supply and/or within cellularcompartments or organs. The liver is a principal site of drugmetabolism. The metabolic process can be broken down into synthetic andnonsynthetic ractions. In nonsynthetic reactions, the drug is chemicallyaltered by oxidation, reduction, hydrolysis, or any combination of theaforementioned processes. These processes are collectively referred toas Phase I reactions.

In Phase II reactions, also known as synthetic reactions orconjugations, the parent drug, or intermediate metabolites thereof, arecombined with endogenous substrates to yield an addition or conjugationproduct. Metabolites formed in synthetic reactions are, typically, morepolar and biologically inactive. As a result, these metabolites are moreeasily excreted via the kidneys (in urine) or the liver (in bile).Synthetic reactions include glucuronidation, amino acid conjugation,acetylation, sulfoconjugation, and methylation.

BRIEF SUMMARY OF THE INVENTION

The subject invention provides materials and methods for the safe andeffective inhibition of serotonin reuptake. In a preferred embodiment,the subject invention provides therapeutic compounds for the treatmentof depression. The compounds of the subject invention can be used totreat at-risk populations, thereby bringing relief of symptoms,improving the quality of life, preventing acute and long-termcomplications, and treating accompanying disorders.

Advantageously, the subject invention provides compounds which arereadily metabolized by the physiological metabolic drug detoxificationsystems. Specifically, in a preferred embodiment, the therapeuticcompounds of the subject invention contain an ester group, which doesnot detract from the ability of these compounds to provide a therapeuticbenefit, but which makes these compounds more susceptible to degradationby hydrolases, particularly serum and/or cytosolic esterases. Thesubject invention further provides methods of treatment comprising theadministration of these compounds to individuals in need of treatmentfor depression.

In a further embodiment, the subject invention pertains to the breakdownproducts which are formed when the therapeutic compounds of the subjectinvention are acted upon by esterases. These breakdown products can beused as described herein to monitor the clearance of the therapeuticcompounds from a patient.

In yet a further embodiment, the subject invention provides methods forsynthesizing the therapeutic compounds of the subject invention.

This invention is drawn to compounds which are more easily metabolizedby the metabolic drug detoxification systems. This invention is alsodrawn to methods of treating disorders, such as obsessive compulsivedisorder, depression, or disorders associated with serontonergichypofunction. Specifically, this invention provides analogs of drugswhich have been designed to be more susceptible to degradation byhydrolases, particularly serum and/or cytosolic esterases and methods oftreatment comprising the administration of these analogs to individuals.

DETAILED DISCLOSURE OF THE INVENTION

The subject invention provides materials and methods for the treatmentof depression and other disorders related to serotonin re uptake.Advantageously, the therapeutic compounds of the subject invention arestable in storage but have a relatively short half-life in thephysiological environment; therefore, the compounds of the subjectinvention can be used with a lower incidence of side effects andtoxicity.

In a preferred embodiment of the subject invention, therapeuticcompounds are provided which are useful in the treatment of depressionand which contain moiety, such as an ester group, which is susceptableto degradation by hydrolases, thereby breaking down the compound andfacilitating its efficient removal from the treated individual. In apreferred embodiment, the therapeutic compounds are metabolized by thePhase I drug detoxification system.

A further aspect of the subject invention pertains to the breakdownproducts which are produced when the therapeutic compounds of thesubject invention are acted upon by a hydrolase. The presence of thesebreakdown products in the urine or serum can be used to monitor the rateof clearance of the therapeutic compound from a patient.

Degradation of the compounds of the subject invention by enzymes such ashydrolases (esterases, peptidases, lipases, glycosidases, phosphateases,etc.) is particularly advantageous for drug metabolism because theseenzymes are ubiquitously distributed and their activity is not dependenton age, gender, or disease state to the same extent as oxidative hepaticdrug metabolism.

The subject invention further provides methods of synthesizing theunique and advantageous therapeutic compounds of the subject invention.Particularly, methods of producing less toxic therapeutic agentscomprising introducing ester groups into therapeutic agents (targetdrugs) are taught. The ester linkage may be introduced into the compoundat a site which is convenient in the manufacturing process for thetarget drug. Additionally, the sensitivity of the ester linkage may bemanipulated by the addition of side groups which hinder or promote thehydrolytic activity of the hydrolases responsible for cleaving the drug.Methods of adding such side groups, as well as the side groupsthemselves, are well known to the skilled artisan and can be readilycarried out utilizing the guidance provided herein.

The subject invention further provides methods of treating disorders,such as depression comprising the administration of a therapeuticallyeffective amount of esterified fluvoxamine analogs to an individual inneed of treatment. Fluraxamine and various related compounds aredescribed in, for example, U.S. Pat. No. 4,085,225 which is incorporatedherein in its entirety by reference. Accordingly, the subject inventionprovides esterified fluvoxamine analogs and pharmaceutical compositionsof these esterified compounds.

This invention is also drawn to methods of treating depression,disorders associated with serontonergic hypofunction, and affectivedisorders, such as obsessive compulsive disorder, comprising theadministration of a therapeutically effective amount of the esterifiedfluvoxamine analog compounds to an individual in need of treatment. Theinvention is also applicable to other disorders associated withserotonin hypofunction (see U.S. Pat. Nos. 5,686,447 and 5,770,740hereby incorporated by reference in their entireties).

In a preferred embodiment, the compounds of the subject invention havethe following structure:

where:

R₁ and R₂ are independently H or C₁₋₁₀ alkyl or R₁ and R₂ are methylenegroups that together form part of a cyclic structure;

R₃ is a linear or branched alkyl or heteroalkyl group having 1 to 12carbon atoms, or R₃ is heterocycloalkyl, benzyl, aryl, or heteroaryloptionally substituted with one or more halogen atoms, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, cyano, amino, alkylamino, dialkylamino,trifluoromethyl, —COOH, or —COOC₁₋₄ alkyl;

X is fluoro, chloro, iodo, trifluoromethyl, methoxy, cyano, nitro,amino, mono- or di-substituted amino, carboxamide, carboxylic acid,carboxylic ester, sulfonic acid, methyl sulfonate, or sulfonamide;

n is from 0 to 12,

Z=—CH₂—CH₂—N(R₆R₇) where R₆ and R₇ are independently H or lower alkyl,or R₆ and R₇ are methylene groups that together with the nitrogen form acyclic structure; or

Z=

where m=1 or 2 and R₈ is H or lower alkyl.

In specific examples, Z can be:

In one embodiment, the oxime ether compounds of the subject inventionhave the following structure:

X is fluoro, chloro, iodo, trifluoromethyl, methoxy, cyano, nitro,amino, mono- or di-substituted amino, carboxamide, carboxylic acid,carboxylic ester, sulfonic acid, methyl sulfonate, or sulfonamide.

n is from 0 to 12, preferably from 0 to 6, and more preferably from 0 to4,

R₁ and R₂ are, independently, H, C₁₋₁₀ alkyl, or R₁ and R₂ are methylenegroups that are part of a cyclic structure, such cyclic structure being,for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Thecyclic structure can also be substituted with 1 to 4 alkyl groups.

Y can be OR₃, where R₃ is a linear or branched alkyl group having 1 to12 carbon atoms, or R₃ is benzyl, substituted benzyl, aryl, heteroaryl,substituted aryl, or substituted heteraryl.

Y can also be NR₄R₅ where R₄ and R₅ are independently H, methyl, ethyl,or R₄ and R₅ are methylene groups that are part of a cyclohexyl ring.The cyclohexyl ring can in turn be substituted with 1 to 4 alkyl groups.

Pharmaceutically acceptable acids include fumarate, maleate, citrate,hydrochloride, phosphate, and gluconate.

The compounds of this invention have therapeutic properties similar tothose of the unmodified parent compounds. Accordingly, dosage rates androutes of administration of the disclosed compounds are similar to thosealready used in the art and known to the skilled artisan (see, forexample, Physicians' Desk Reference, 54^(th) Ed., Medical EconomicsCompany, Montvale, N.J., 2000).

The compounds of the subject invention can be formulated according toknown methods for preparing pharmaceutically useful compositions.Formulations are described in detail in a number of sources which arewell known and readily available to those skilled in the art. Forexample, Remington's Pharmaceutical Science by E. W. Martin describesformulations which can be used in connection with the subject invention.In general, the compositions of the subject invention will be formulatedsuch that an effective amount of the bioactive compound(s) is combinedwith a suitable carrier in order to facilitate effective administrationof the composition.

In accordance with the invention, pharmaceutical compositionscomprising, as an active ingredient, an effective amount of one or moreof the compounds and one or more non-toxic, pharmaceutically acceptablecarrier or diluent. Examples of such carriers for use in the inventioninclude ethanol, dimethyl sulfoxide, glycerol, silica, alumina, starch,and equivalent carriers and diluents.

Further, acceptable carriers can be either solid or liquid. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances which may act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents or an encapsulating material.

The disclosed pharmaceutical compositions may be subdivided into unitdoses containing appropriate quantities of the active component. Theunit dosage form can be a packaged preparation, such as packetedtablets, capsules, and powders in paper or plastic containers or invials or ampoules. Also, the unit dosage can be a liquid basedpreparation or formulated to be incorporated into solid food products,chewing gum, or lozenge.

The term “individual(s)” is defined as a single mammal to which isadministered a compound of the present invention. The mammal may be arodent, for example a mouse or rat, pig, horse, rabbit, goat, pig, cow,cat, dog, or human. In a preferred embodiment, the individual is ahuman.

Following are examples which illustrate procedures for practicing theinvention. These examples should not be construed as limiting. Allpercentages are by weight and all solvent mixture proportions are byvolume unless otherwise noted.

An exemplary reaction scheme for the production of esterifiedfluvoxamine compounds, such as5-methyl-5-oxo-4′-trifluoromethylvalerophenone O-(2-aminoethyl oxime,hydrochloride is provided below.

-   (i) 4-bromobenzotrifluoride 1 reacts with butyl lithium at −70° C.    in anhydrous THF to give the lithium salt 2. (ii) The lithium salt    reacts with copper(I) iodide to form the lithium diaryl cuprate    complex 3 at −40° C. (iii) The complex 3 in turn reacts with methyl    glutaryl chloride to form the valerophenone 4. (iv) Compound 4 forms    an oxime with 2-aminooxyethylamine, dihydrochloride, in pyridine and    absolute ethanol at reflux temperature to form the target compound    5.

The number of methylene groups between the terminal carboxyl and theoxime moiety can be controlled in step (iii). In the above describedreaction scheme, the number of methylene groups is (CH₂)_(n), where n isequal to 3. By using methyl succinyl chloride in step (iii) instead ofmethyl glutaryl chloride, then one obtains n=2. Similarly, by usingmethyl malonyl chloride, then n=1.

Modifications of the compounds disclosed herein can readily be made bythose skilled in the art. Thus, analogs, and salts of the exemplifiedcompounds are within the scope of the subject invention. With aknowledge of the compounds of the subject invention, and theirstructures, skilled chemists can use known procedures to synthesizethese compounds from available substrates.

As used in this application, the term “analogs” refers to compoundswhich are substantially the same as another compound but which may havebeen modified by, for example, adding additional side groups. The term“analogs” as used in this application also may refer to compounds whichare substantially the same as another compound but which have atomic ormolecular substitutions at certain locations in the compound.

Analogs of the exemplified compounds can be readily prepared usingcommonly known, standard reactions. These standard reactions include,but are not limited to, hydrogenation, methylation, acetylation, andacidification reactions. For example, new salts within the scope of theinvention can be made by adding mineral acids, e.g., HCl, H₂SO₄, etc.,or strong organic acids, e.g., formic, oxalic, etc., in appropriateamounts to form the acid addition salt of the parent compound or itsderivative. Also, synthesis type reactions may be used pursuant to knownprocedures to add or modify various groups in the exemplified compoundsto produce other compounds within the scope of the invention.

It should be understood that the examples, reaction schemes, andembodiments described herein are for illustrative purposes only and thatvarious modifications or changes in light thereof will be suggested topersons skilled in the art and are to be included within the spirit andpurview of this application and the scope of the appended claims.

1. A method for treating a disease state which can be improved by aserotonin reuptake inhibitor wherein said method comprisesadministering, to an individual in need of such treatment, a compound,or salt thereof, wherein said compound has the following structure

and wherein R₁ and R₂ are independently H or C₁₋₁₀ alkyl; or R₁ and R₂are methylene groups that together form part of a cyclic structure; R₃is a linear or branched alkyl or heteroalkyl group having 1 to 12 carbonatoms; or R₃ is heterocycloalkyl, benzyl, aryl, or heteroaryl optionallysubstituted with one or more halogen atoms C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy, cyano, amino, alkylamino, dialkylamino, trifluoromethyl,— COOH,or —COOC₁₋₄ alkyl; X is fluoro, chloro, iodo, trifluoromethyl, methoxy,cyano, nitro, amino, mono- or di-substituted amino, carboxamide,carboxylic acid, carboxylic ester, sulfonic acid, methyl sulfonate, orsulfonamide; n is from 0 to 12, and Z=


2. A pharmaceutical composition comprising a compound, or a saltthereof, wherein said compound has the following structure:

where R₁ and R₂ are independently H or C₁₋₁₀ alkyl or R₁ and R₂ aremethylene groups that together form part of a cyclic structure; R₃ is alinear or branched alkyl or heteroalkyl group having 1 to 12 carbonatoms, or R₃ is heterocycloalkyl, benzyl, aryl, or heteroaryl optionallysubstituted with one or more halogen atoms, C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy, cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH,or —COOC₁₋₄ alkyl; X is fluoro, chloro, iodo, trifluoromethyl, methoxy,cyano, nitro, amino, mono- or di-substituted amino, carboxamide,carboxylic acid, carboxylic ester, sulfonic acid, methyl sulfonate, orsulfonamide; n is from 0 to 12, and Z is selected from the groupconsisting of:


3. A compound, or salt thereof, wherein said compound has the followingstructure:

where: R₁ and R₂ are independently H or C₁₋₁₀ alkyl or R₁ and R₂ aremethylene groups that together form part of a cyclic structure; R₃ is alinear or branched alkyl or heteroalkyl group having 1 to 12 carbonatoms, or R₃ is heterocycloalkyl, benzyl, aryl, or heteroaryl optionallysubstituted with one or more halogen atoms, C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy, cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH,or —COOC₁₋₄ alkyl; X is fluoro, chloro, iodo, trifluoromethyl, methoxy,cyano, nitro, amino, mono- or di-substituted amino, carboxamide,carboxylic acid, carboxylic ester, sulfonic acid, methyl sulfonate, orsulfonamide; n is from 0 to 12, Z=—CH₂—CH₂—N(R₆R₇) where R₆ and R₇ areindependently H or lower alkyl, or R₆ and R₇ are methylene groups thattogether with the nitrogen form a cyclic structure; or Z=

where m=1 or 2 and R₈ is H or lower alkyl.
 4. The compound, according toclaim 3, wherein Z is selected from the group consisting of:


5. The compound, according to claim 3, wherein X is CF₃.
 6. Thecompound, according to claim 3, wherein n is from 0 to 4.